Project Summary/Abstract Understanding the mechanisms involved in HIV acquisition and transmission is critical for novel prevention strategies. The understanding of early events in HIV-1 acquisition and expansion of the virus remains incomplete, especially in males. The incidence of sexually transmitted infections (STI?s) can increase HIV-1 acquisition risk, and there exist gaps in understanding the mechanisms also. This study will exploit the medical male circumcision (MMC) roll out in South Africa, which facilitates the collection of otherwise discarded foreskins to characterize male genital tissue-resident HIV-1 target cells. Dr Chigorimbo-Tsikiwa will characterize the molecular and functional interactions between HIV-1 , lymphoid and myeloid target cells from the FS. A uniqueness of the proposed study lies in interrogating how in vivo activating events from bacterial STIs can modulate ex vivo HIV-1 target cell susceptibility. We hypothesize that foreskin tissue contains several cell lineages that are susceptible to HIV-1 infection that can support viral expansion and that the increased inflammatory response induced by asymptomatic STIs will exacerbate this susceptibility. Aim 1 will investigate the phenotypic and transcriptomic profiles between lymphoid and myeloid cells isolated from the foreskin tissues from men with and without asymptomatic bacterial STIs. Aim 2, will determine the impact of immune activation on the susceptibility of lymphoid and myeloid cells to HIV-1 infection. Dr Chigorimbo-Tsikiwa will challenge foreskin-derived cells with a panel of HIV-1 isolates to assess the relative susceptibility of characterized cells to HIV-1 infection. We will explore the impact of in vivo immune activation by performing HIV-1 challenge on cells isolated from STI-positive individuals as well as to in vitro activation using Chlamydia antigens, LPS and TLR agonists on viral infectivity and expansion. Interferon stimulated genes, (ISG?s) antagonists have been shown to confer an antiviral state in cells and against other retroviruses. Therefore, aim 3 will assess the repurposing of bis-arylidenecycloalkanones as ISG agonist for use as anti -HIV-1 molecules in various cell models. This research study based from human foreskins will provide novel insights in HIV acquisition and transmission in the male genital tract and increase knowledge in the field which will facilitate the research career development of Dr Chigorimbo- Tsikiwa. Dr Chigorimbo-Tsikiwa will receive mentorship from lead researchers who are prolific publishers, possess several research grants in infectious disease biomedical research who have mentored approximately 40 post-docs between them in Dr David Russell at Cornell University, Dr Frank Kirchhoff at Ulm University in Germany and Dr Clive Gray in South Africa. This study will allow Dr Chigorimbo-Tsikiwa access to high technology driven research in three continents afforded by her mentorship relationships during this K award spring boarding her as an independent African HIV biomedical scientist.